Pharmaceutical composition for once a day administration of trospium chloride

ABSTRACT

A pharmaceutical composition of a pharmaceutically acceptable trospium salt, with upon administration to a human patient generates an average steady state blood levels of trospium with a minimum (C min ) and maximum (C max ) blood levels of about 0.5-2.5 ng/ml and about 2.0-6.0 ng/ml, respectively.

This application is a continuation of U.S. patent application Ser. No.10/980,818, filed Nov. 4, 2004, and claims priority to provisionalapplication Nos. 60/517,198, filed Nov. 4, 2003, and 60/523,968 filedNov. 21, 2003, the contents of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions thatallow for once daily dosage forms of trospium. Trospium is indicated inthe treatment of urinary frequency, urgency, nocturia, andurge-incontinence associated with detrusor instability, urge syndrome,and detrusor hyperreflexia. These compositions are useful in treatingthe afore-mentioned conditions with once-a-day administration.

BACKGROUND OF THE INVENTION

Trospium is a quaternary ammonium derivative of tropine, and hasanticholinergic properties. The hydrophilicity of the molecule, due toits permanent positive charge, limits its lipid solubility. Trospiumchloride has been shown to antagonize acetylcholine on excised strips ofhuman bladder muscle. Antispasmodic activity has been shown in thebladder, the small intestine, and on contractility of the gall bladder.Trospium chloride exhibits parasympatholytic action by reducing smoothmuscle tone, such as is found in the urogenital and gastrointestinaltracts. This mechanism enables the detrusor to relax, thus inhibitingthe evacuation of the bladder. Lowering the maximum detrusor pressureresults in improved adaptation of the detrusor to the contents of thebladder, which in turn leads to enhanced bladder compliance withincreased bladder capacity.

Trospium chloride was introduced into the market as a spasmolytic agentin 1967 (German patent 1 194 422). Trospium chloride has been availablein an orally administrable, solid administration form (tablets anddragees), for intravenous or intramuscular injection as a solution, andfor rectal administration as suppositories, and is primarily used forthe treatment of bladder dysfunctions (urge incontinence, detrusorhyperreflexia). The product has been on the market in Germany andseveral other European countries for a number of years for specifictherapeutic indications including urinary frequency, urgency, nocturia,and urge-incontinence associated with detrusor instability, urgesyndrome, and detrusor hyperreflexia.

Currently, in the European market there is an immediate release trospiumchloride tablet (Spasmo-lyt®), which is indicated for the treatment ofurge incontinence and detrusor hyperreflexia and is used as a 20 mgtablet taken twice daily or bid (a total dose of 40 mg per day). Incommon with other quaternary ammonium compounds, orally administeredtrospium chloride is slowly absorbed, with the maximum blood levelachieved after 5-6 hrs. The oral bioavailability is approximately 10%,and is significantly reduced with the intake of high-fat food. There areside effects associated with the use of the twice-daily trospiumchloride regimen, such as dry mouth, headache, constipation, dyspepsia,and abdominal pain. These side effects are associated with a high bloodconcentration of trospium chloride. Moreover, studies in which a 40 mgimmediate release dose was given once daily resulted in higher overallincidence of adverse events as compared to 20 mg given twice daily.

A once-a-day administration of trospium is advantageous over thetwice-a-day administration in terms of both patient compliance andreduced adverse events, thus providing better treatment of theconditions for which trospium chloride is indicated.

In order to provide for an effective once-a-day form of trospium, thereis a need for unique formulation approaches that provide the desiredtherapeutic effects while minimizing, if not eliminating, the undesiredside effects mentioned above. This means that the minimum blood trospiumconcentration (C_(min)) at steady state should be above the minimumtherapeutically effective blood concentration and the maximum bloodtrospium concentration (C_(max)) also at steady state should be belowthe maximum toxic blood concentration over the treatment period.Trospium chloride and other quaternary ammonium compounds exhibit alimited window of absorption in the human gastrointestinal tract,presenting a significant challenge to formulating a once-a-daycomposition.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a pharmaceuticalcomposition of any pharmaceutically acceptable trospium salt, typicallytrospium chloride, which can be given once a day yet meet the steadystate blood levels required for the treatment or prevention of diseasesor conditions that would benefit from its spasmolytic activity. Such adisease or condition includes, and the present invention is primarilydirected to, such bladder dysfunctions as urge incontinence or detrusorhyperreflexia, nocturia, and urinary frequency.

Such once-daily compositions of a trospium salt are targeted to resultin average steady state blood levels of trospium with a minimum(C_(min)) and maximum (C_(max)) blood levels of about 0.5-2.5 ng/ml andabout 2.0-6.0 ng/ml, respectively, which blood levels have been shown tobe safe and effective. Steady state blood levels preferably averagebetween a C_(min) of about 0.75 ng/ml and a C_(max) of about 5.0 ng/ml,for dosage forms of the present invention that correspond to a 20 mg bidregimen.

In one aspect of the invention an extended release (XR) pharmaceuticalcomposition is provided, which contains between about 25 mg and about 60mg trospium chloride for once-a-day or qd administration, and which ischaracterized by having the following in vitro release profile inphosphate buffer (pH 7.5) dissolution medium: about 0-40% released inabout 1 hour, about 20-85% released in about 4 hours and greater than70% released in about 12 hours.

In yet another aspect of this invention a delayed release (DR)pharmaceutical composition is provided, which contains between about 25mg and about 80 mg trospium chloride for once-a-day or qdadministration, depending on the length of the lag phase. The in vivodelay in the release can be tailored to a particular application, butgenerally is from about 0.5 hour to about 6 hours, more preferably fromabout 2.5 hours to about 5 hours, during which time there shouldminimal, if any, detectable trospium in the blood. The in vitro releaseprofile of such a formulation is generally characterized by having lessthan about 10% released in acidic media within 2 hours and more thanabout 80% released in buffer media of pH 6.8 and higher within 1 hour.

In still another aspect of the present invention an immediate release(IR) composition is provided, which contains no more than about 20 mgactive drug, combined with a delayed release composition that isdesigned to dissolve at a pH of about 7.0 (i.e., in the lower part ofthe GI tract), such as the DR2 composition of the examples, to form asingle once-a-day trospium chloride formulation containing in totalabout 80 mg drug.

Another aspect of the present invention is to provide a method fortreating urinary frequency, urgency, nocturia, and urge-incontinenceassociated with detrusor instability, urge syndrome, and detrusorhyperreflexia with once-a-day administration of trospium chloride.

Yet another aspect of the invention provides a single dosage form thatallows for an additional release, or pulse, of a drug with a shorthalf-life at about the half-life (t_(1/2)) thereof. Such dosage formsare a significant challenge to develop when the drug is one, such astropsium, that has a defined region of absorption in the upper GI tract,and is more poorly absorbed in the lower GI tract (i.e. the ileum areaand colon).

The invention is also directed to a method of enteral administration ofa pharmaceutical composition comprising an effective amount of a salt oftrospium (e.g., trospium chloride), in which an improvement comprisesincluding a delayed release formulation of said salt of trospium, whichreleases trospium at a pH of about 7.0. In another embodiment of theinvention, a method is provided for an enteral administration of apharmaceutical composition comprising an effective amount of a trospiumsalt (e.g., trospium chloride), in which an improvement comprisesincluding a delayed release formulation of said trospium salt, whichreleases trospium in the lower intestine, preferably in the colon.Accordingly, the invention is further directed to a pharmaceuticalcomposition comprising a trospium salt (preferably, trospium chloride)as at least one active pharmaceutical ingredient in which at least aportion of said trospium salt is contained in a delayed releaseformulation, which releases trospium at a pH of about 7.0. In analternative embodiment, the invention is still further directed to apharmaceutical composition comprising a trospium salt (preferably,trospium chloride) as at least one active pharmaceutical ingredient inwhich at least a portion of said trospium salt is contained in a delayedrelease formulation, which releases trospium in the lower intestine,colon, or both.

Finally, another aspect of the invention is to provide processes forpreparing the once daily compositions of the present invention, andmethods of treatment using them.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profiles for the immediate release trospiumchloride pellets in 0.1N HCl, pH 1.1. The profiles show a release thatreaches completion in about 15 minutes.

FIG. 2 shows the dissolution profiles for ethylcellulose coated(extended release or “XR”) trospium pellets.

FIG. 3 shows the dissolution profiles for trospium chloride delayedrelease (“DR”) pellets.

FIG. 4 shows the mean dissolution profile for 40 mg trospium chlorideXR1-2 pellets.

FIG. 5 shows the mean dissolution profile for 50 mg trospium chlorideXR1-1 pellets.

FIG. 6 shows the mean dissolution profile for 35 mg trospium chlorideDR1 pellets.

FIG. 7 shows the mean dissolution profile for 40 mg trospium chlorideDR2 pellets.

FIG. 8 shows the mean dissolution profile for 60 mg trospium chlorideXR1/DR2 pellets.

FIG. 9 shows the pharmacokinetic profiles of four exemplary controlledrelease compositions versus two immediate release products.

FIG. 10 shows the same data illustrated in FIG. 4 with Formulation Dremoved for ease of comparison.

FIG. 11 shows the steady state pharmacokinetic profiles of four trospiumchloride controlled release formulations.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is primarily directed to once-daily, orallyadministrable forms of trospium, which due to its charged nature isusually found in the form of a salt, typically trospium chloride. Suchformulations have not been previously known, most likely becausetrospium chloride presents challenges due to its high solubility andlimited absorption window. Moreover, previous researchers have notedthat due to the limited region of absorption, conventional modifiedrelease dosage forms were not thought practical. See, e.g., Schröder, S.et al. (Institute for Pharmacology, Clinical Pharmacology, University ofK Īn and Madaus AG, Köln, Germany). However, the present inventors havediscovered oral dosage forms, which can be given once a day yet meet thesteady state blood levels required for the treatment or prevention ofdiseases or conditions that would benefit from its spasmolytic activity.

The present invention is accomplished by providing an orallyadministered composition of trospium designed to provide certain steadystate blood levels of the drug comparable to a twice-a-day regimen,preferably with some refinements, yet in a formulation that requiresthat the mammal, preferably human, take only one dosage a day. Thepreferred blood level of trospium is between about 0.5 and about 6.0ng/ml at the steady state. Preferably, the blood levels stay within thepreferred blood level, with once daily dosing, for the course oftreatment. More preferably, the blood levels are between about 0.5 ng/mland 5.0 ng/ml at the steady state. In addition, more preferably, asuitable once-a-day formulation exhibits a C_(max) within 80 to 120% ofthe average C_(max) of a corresponding twice-a-day formulation(typically one 20 mg IR twice a day, but could be titrated up or down)and a C_(min) between 80 and 120% of the average C_(min) of said twicedaily regimen.

The concepts of the present invention may likewise be used to formulatecontrolled release compositions containing therapeutically active agentsthat exhibit similar solubility, limited absorption window andbioavailability characteristics as trospium. Examples of such compoundsinclude, for instance, propantheline, emepronium, clidinium, andglycopyrrolate, which all are quaternary ammonium compounds.

As used herein, “about” means within the pharmaceutically acceptablelimits found in the United States Pharmacopia (USP-NF 21), 2003 AnnualEdition, or available at www.usp.org, for amount of activepharmaceutical ingredients. With respect to blood levels, “about” meanswithin FDA acceptable guidelines.

The compositions of the present invention may be in the form of, amongothers, a granule, tablet (including matrix or osmotic), pellet, powder,sachet, capsule, gel, dispersion, solution or suspension. The onlyrequirement is that the dosage forms be composed in such a manner as toachieve the profiles set forth herein.

In vivo profiles for trospium chloride that provide the appropriateblood (or, more particularly, plasma) concentration levels over time inorder to meet the therapeutic requirements for once daily administrationwere determined in the present invention. The method used herein for theplasma concentration determination was the liquid chromatography/massspectrometry/mass spectrometry or LC/MS/MS method. With this technique,trospium is extracted from an aliquot of plasma using a solid phaseextraction procedure. This extract is then analyzed using HPLC equippedwith a mass spectrometer as a detector. These profiles are such that themean blood trospium chloride levels provide an effective amount of thedrug for the treatment of such conditions as urinary frequency, urgency,nocturia, and urge-incontinence due to detrusor instability, urgesyndrome, and detrusor hyperreflexia, yet within such upper limits as tominimize the occurrence of adverse side effects typically associatedwith spikes in the plasma concentration that follow the multipleadministration of immediate release formulations. The blood trospiumchloride concentrations versus time profiles are characterized by asteady state C_(min) of from about 0.5 to about 1.5 ng/ml, and a steadystate C_(max) of from about 2.0 to about 6.0 ng/ml.

With the present invention, it was surprisingly found that once dailydosing of trospium chloride in a delayed release formulation providesthe required blood profile. Moreover, it was surprisingly found thatonce daily dosing with a dosage unit containing a combination ofimmediate release and delayed components provides a desired therapeuticblood profile. Still further, it was discovered that once daily dosingof trospium chloride in an extended release preparation also provides adesired therapeutically effective blood profile.

Thus, with the present invention it was found that an effective bloodtrospium chloride concentration at steady state could be achieved byformulating trospium chloride in several inventive ways. These dosageunits are in the form of an extended release, a delayed release, orvarious combinations of immediate, extended and delayed release forms.

Immediate Release Composition

By “immediate release composition” is meant a dosage form that isformulated to release substantially all the active ingredient onadministration with no enhanced, delayed or extended release effect.Such a composition for purposes of the present invention is, at leastinitially, in the form of a pellet (a term used interchangeably with“bead” or “beadlet” herein). The immediate release pellet can be onecomponent of a plurality of components of a dosage form. The immediaterelease pellet can also serve as a precursor to an extended or delayedrelease pellet.

The non-active ingredients and processes for preparing such immediaterelease pellets are well known in the art, and the present invention isnot limited in these respects. See, for example, Remington'sPharmaceutical Sciences, 18^(th) Edition, A. Gennaro, Ed., Mack Pub. Co.(Easton, Pa. 1990), Chapters 88-91, the entireties of which are herebyincorporated by reference.

For instance, an immediate release pellet can be prepared by mixing thetrospium salt (e.g., trospium chloride) with a bulking agent.Additionally, one can add disintegrating agents, antiadherants andglidants to the formulation.

Bulking agents employable in these compositions may be chosen from,among others: microcrystalline cellulose, for example, AVICEL® (FMCCorp.) or EMCOCEL® (Mendell Inc.), which also has binder properties;dicalcium phosphate, for example, EMCOMPRESS® (Mendell Inc.); calciumsulfate, for example, COMPACTROL® (Mendell Inc.); and starches, forexample, Starch 1500; and polyethylene glycols (CARBOWAX®). Such bulkingagents are typically present in the range of about 5% to about 75%(w/w), with a preferred range of about 25% to about 50% (w/w).

Suitable disintegrants include, but are not limited to: crosslinkedsodium carboxymethyl cellulose (AC-DI-SOL®), sodium starch glycolate(EXPLOTAB® PRIMOJEL®) and crosslinked polyvinylpolypyrrolidone(Plasone-XL®). Disintegrants are used to facilitate disintegration ofthe pellet upon administration and are typically present in an amount ofabout 3% to about 15% (w/w), with a preferred range of about 5% to about10% (w/w).

Antiadherants and glidants employable in such formulations can includetalc, cornstarch, silicon dioxide, sodium lauryl sulfate, colloidalsilica dioxide, and metallic stearates, among others.

In addition, the immediate release composition may contain one or morebinders to give the pellets cohesiveness. Such binders are well known inthe art, and include such substances as microcrystalline cellulose,polyvinyl pyrrolidone, starch, Maltrin, methylcellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, sucrose solution, dextrosesolution, acacia, tragacanth and locust bean gum, which may be appliedwet. The binding agent may be present in the composition in an amount offrom about 0.2 wt % to about 20 wt %, preferably from about 5 wt % toabout 15 wt %.

The pellets can be made by, for example, simple granulation such as wetgranulation or dry granulation, followed by sieving; extrusion andmarumerization (spheronization); rotogranulation; or any agglomerationprocess that results in a pellet of reasonable size and robustness. Forextrusion and marumerization, the drug and other additives aregranulated by addition of a binder solution. The wet mass is passedthrough an extruder equipped with a certain size screen, and theextrudates are spheronized in a marumerizer. The resulting pellets aredried and sieved for further applications.

One may also use high-shear granulation, wherein the drug and otheradditives are dry-mixed and then the mixture is wetted by addition of abinder solution in a high shear-granulator/mixer. The granules arekneaded after wetting by the combined actions of mixing and milling. Theresulting granules or pellets are dried and sieved for furtherapplications.

Alternatively, and preferably, the immediate release beadlets or pelletsare prepared by solution or suspension layering, whereby a drug solutionor dispersion, with or without a binder and optionally an anti-tackingagent such as talc, is sprayed onto a core or starting seed (eitherprepared or a commercially available product) in a fluid bed processoror other suitable equipment. The cores or starting seeds can be, forexample, sugar spheres or spheres made from microcrystalline cellulose.The binder in the formula can be present in amounts ranging from about0% to about 5% by weight, and preferably about 0.5% to about 2% byweight. The amount of anti-tacking agent used can be from about 0% toabout 5%, preferably about 0.5% to about 2% by weight. The drug thus iscoated on the surface of the starting seeds. The drug may also belayered onto the drug-containing pellets described above, if desired.Following drug layering, the resulting drug-loaded pellets are dried forfurther applications.

A protective layer, or overcoating, may be desired to ensure that thedrug-loaded pellets do not aggregate during processing or upon storage.The protective coating layer may be applied immediately outside thecore, either a drug-containing core or a drug-layered core, byconventional coating techniques such as pan coating or fluid bed coatingusing solutions of polymers in water or suitable organic solvents or byusing aqueous polymer dispersions. OPADRY® (polyethylene glycols),OPADRY II® (Colorcon) and corresponding color and colorless grades fromColorcon can be used to protect the pellets from being tacky and providecolors to the product. The suggested levels of protective or colorcoating are from about 1% to about 6%, preferably about 2% to about 3%(w/w). Many ingredients can be incorporated into the overcoatingformula, for example to provide a quicker immediate release, such asplasticizers: acetyltriethyl citrate, triethyl citrate, acetyltributylcitrate; dibutylsebacate, triacetin, polyethylene glycols, propyleneglycol and the others; lubricants: talc, colloidal silica dioxide,magnesium stearate, calcium stearate, titanium dioxide, magnesiumsilicate, and the like.

The immediate release pellets are contemplated as being used incombination with extended release pellets and/or delayed release pelletsin a single dosage form.

Extended Release Composition (XR)

Trospium chloride extended release pellets can be prepared, for example,by coating drug layered inert pellets with release controlling polymers.First, the inert pellet is coated with the drug layer or a drug loadedgranule is prepared, as described above. Then the active (drug loaded)pellet is coated with a release controlling polymeric membrane. Therelease controlling coating layer may be applied immediately outside thecore (such as a drug-containing core or a drug-layered core), byconventional coating techniques, such as pan coating or fluid bedcoating, using solutions of polymers in water or suitable organicsolvents or by using aqueous polymer dispersions. As an alternativeembodiment, the release controlling membrane can separate additionaldrug layers on the core; for instance, after coating with the releasecontrolling substance, another drug layer can be applied, which isfollowed by another release controlling layer, etc. Suitable materialsfor the release controlling layer include EUDRAGIT® RL (copolymers ofacrylic and methacrylic acid esters), EUDRAGIT® RS (copolymers ofacrylic and methacrylic acid esters), cellulose derivatives such asethylcellulose aqueous dispersions (AQUACOAT®, SURELEASE®), hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer,OPADRY®, and the like. The thickness of the coating affects the releaseprofile, and so this parameter can be used to customize the profile. Thesuggested coating levels are from about 1% to about 40%, preferablyabout 5% to about 30% (w/w), and about 20% or about 25% as mostpreferred embodiments. A 20% w/w coating should release about 80% of thetrospium chloride in 3.5 hours post ingestion, and a 25% w/w coatingshould result in the release of about 80% of the trospium chloride in4.5 hours post-ingestion.

The extended release pellets contain between about 25 and about 60 mgtrospium chloride, and may be used alone, or in combination withimmediate release or delayed release pellets to constitute a singledaily dosage form.

Delayed Release Composition (DR)

The delayed-release component has a coat applied to the surface of theactive pellet that delays the release of the drug from the pellet afteradministration for a certain period of time. This delayed release isaccomplished by applying a coating of enteric materials. “Entericmaterials” are polymers that are substantially insoluble in the acidicenvironment of the stomach, but are predominantly soluble in intestinalfluids at various specific pHs. The enteric materials are non-toxic,pharmaceutically acceptable polymers, and include, for example,cellulose acetate phthalate (CAP), hydroxypropyl methylcellulosephthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetatetrimellitate, hydroxypropyl methylcellulose succinate, cellulose acetatesuccinate, cellulose acetate hexahydrophthalate, cellulose propionatephthalate, copolymer of methylmethacrylic acid and methyl methacrylate,copolymer of methyl acrylate, methylmethacrylate and methacrylic acid,copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series),ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethylacrylate copolymer, natural resins such as zein, shellac and copalcollophorium, carboxymethyl ethylcellulose, co-polymerized methacrylicacid/methacrylic acid methyl esters such as, for instance, materialsknown under the trade name EUDRAGIT®L12.5, L100, or EUDRAGIT®S12.5,S100, and several commercially available enteric dispersion systems(e.g., EUDRAGIT® L30D55, EUDRAGIT® FS30D, EUDRAGIT® L100-55, EUDRAGIT®S100 (Rohm Pharma), KOLLICOAT® MAE30D and 30DP (BASF), ESTACRYL® 30D(Eastman Chemical), AQUATERIC® and AQUACOAT® CPD30 (FMC)). The foregoingis a list of possible materials, but one of skill in the art wouldappreciate that there are other such materials that would meet theobjectives of the present invention of providing for a delayed releaseprofile including tailoring release based on the ambient pH environment,temporal considerations and other factors.

These coating materials can be employed in coating the surfaces in arange of from about 1.0% (w/w) to about 50% (w/w) of the pelletcomposition. Preferably, these coating materials are in the range offrom about 20 percent to about 40 percent (w/w). The pellets may becoated in a fluidized bed apparatus or pan coating, for example, in aconventional manner.

With the enteric-coated pellets, there is no substantial release oftrospium in the acidic stomach environment of below about pH 4.5. Thetrospium becomes available when the pH-sensitive enteric layer dissolvesat a higher pH in the GI tract, after a certain delayed time, or afterthe unit passes through the stomach. The preferred delay time is in therange of about 0.5 to about 6 hours, but more preferable is about 0.5 toabout 4 hours.

More particularly, preferred DR pellets are those that are coated withEudragit® L30D-55 (which dissolves at about pH 5.5-6.0, i.e., in theupper intestines), and others that are coated with Eudragit FS30D (whichdissolves at about pH 7.0, i.e. in the lower intestine and colon).

As a variation of this embodiment, the DR pellet contains layers of thetrospium, separated by protective (XR) or release-controlling (DR)layers, optionally surrounded by an IR layer, which will result in apulsed dose delivery; in other words, a combination of an IR or XR witha DR in the same pellet. Such a dosage form is made as an alternativeway to meet the blood level requirements of the release profile of thepresent invention, which may be comparable to separate IR/XR and IR/DRpellets in the same capsule.

Preferably, the DR pellets are used in combination with XR pellets, butmay also be used with IR pellets or a combination of all three.

Immediate Release (IR)/Delayed Release(DR) Dosage Units

Pulsatile drug release can be achieved through a combination ofimmediate release and delayed release components in a single dosageform. For instance, a combination of the immediate release (IR) pelletsand delayed release (DR) pellets described herein can be employed. Withthis approach, pellets coated with enteric polymer (DR pellets) arecombined with drug-coated pellets (IR pellets) to provide an immediaterelease followed by a pulsed release of trospium. Whereas the IR portionprovides a fast rise in the plasma-time profile, the DR portion helpsensure that an effective plasma level is maintained over a longer periodof time, preferably a 24 hour period.

The ratio between the immediate-release component and thedelayed-release component can be used to adjust the in vitro drugrelease profile and in vivo blood concentration profile. Moreover, theprofile can be manipulated by the properties of the delayed-releasecoating. By providing the desired drug release profiles according to thepresent invention, the compositions eliminate the need for a second dosefor the day. Additionally, the total dose of trospium is preferably ator below 80 mg to avoid undesirable side effects but more than 30 mg toachieve the desired antispasmodic effect.

Immediate Release (IR)/Extended Release (XR) Dosage Units

As an alternative embodiment, the once-daily dosage unit may contain acombination of IR and XR pellets, in ratios designed to be substantiallyequivalent to a twice a day regimen, or otherwise provide a once-dailydosage form that will be safe and effective with minimized side effects.

The immediate release portion is designed to provide an effective plasmalevel at early time points. The extended release portion of the dosageform is designed to maintain the effective blood level throughout a24-hour period, thus providing coverage for 24 hr. The IR portionprovides about 20 mg or less of trospium to provide effective bloodlevels and yet avoid the side effects associated with spikes in theplasma profile. The extended release portion provides about 20 mg toabout 60 mg of trospium chloride, more preferably from about 20 to about40 mg in the extended release form.

Immediate Release (IR)/Delayed Release (DR)/Extended Release (XR) DosageUnits

Yet another embodiment of the present invention is a multiparticulatedosage form, which combines the three types of pellets. This type ofdosage unit will provide multiple pulses of drug release, with theeffect being a more or less sustained blood level of trospium within theacceptable range.

With this combination, the IR portion is designed to provide aneffective blood level soon after ingestion, which is maintained by theDR and XR combinations. The DR portion provides an immediate releaseafter a delay. The XR portion provides an extended release profile thatmaintains the effective blood level of trospium throughout the course ofthe day. The total dose of trospium in this composition is no greaterthan 80 mg, preferably 60 mg with the IR portion accounting for amaximum of about 20 mg of the total. The DR and XR portions account for10 mg to 60 mg combined with ratios of XR to DR ranging form about 1:10to about 10:1.

Delayed Release (DR)/Extended Release (XR) Dosage Units

Yet another embodiment of the present invention is a multiparticulatedosage form, which combines the extended release pellets with delayedrelease pellets. While the XR portion provides a sustained bloodprofile, the DR portion prevents the blood level form falling below theeffective level at later time points. The XR is designed to providebetween 10 mg to 40 mg, preferably between 20 mg to 40 mg, and morepreferably 30 mg trospium chloride. The DR portion is preferably alonger delayed release with a delay of about 2-4 hrs and providesbetween 10 mg and 40 mg, preferably between 20 mg and 40 mg, and morepreferably 30 mg trospium chloride.

Dosage Forms

As noted previously herein, the compositions of the present inventioncan be in a number of different forms, such as tablets, powders,suspensions, solutions, etc. The composition is preferably inpellet/beadlet form, which can be incorporated into hard gelatin orother kinds of capsules, either with additional excipients, or alone.Typical excipients to be added to a capsule formulation include, but arenot limited to: fillers such as microcrystalline cellulose, soypolysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose,sucrose, sorbitol, or any other inert filler. In addition, there can beflow aids such as fumed silicon dioxide, silica gel, magnesium stearate,calcium stearate or any other materials that impart good flowproperties. A lubricant can also be added if desired, such aspolyethylene glycol, leucine, glyceryl behenate, magnesium stearate orcalcium stearate. The multiparticulate capsules are preferred becausethey provide an increased surface area as opposed to a tablet, whichallows for better release profiles and thus bioavailability.

However, the pellets described above can be incorporated into a tablet,in particular by incorporation into a tablet matrix, which rapidlydisperses the particles after ingestion. In order to incorporate theseparticles into such a tablet, a filler/binder must be used in thetableting process that will not allow the destruction of the pelletsduring the tableting process. Materials that are suitable for thispurpose include, but are not limited to, microcrystalline cellulose(AVICEL®), soy polysaccharide (EMCOSOY®), pre-gelatinized starches(STARCH® 1500, NATIONAL® 1551), and polyethylene glycols (CARBOWAX®).These materials should be present in the range of about 5%-75% (w/w),and preferably between about 25%-50% (w/w).

In addition, disintegrants are added to the tablets in order to dispersethe beads once the tablet is ingested. Suitable disintegrants include,but are not limited to: crosslinked sodium carboxymethyl cellulose(AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), andcrosslinked polyvinylpolypyrrolidone (Plasone-XL). These materialsshould be present in the range of about 3%-15% (w/w), with a preferredrange of about 5%-10% (w/w).

Lubricants are also added to assure proper tableting, and these caninclude, but are not limited to: magnesium stearate, calcium stearate,stearic acid, polyethylene glycol, leucine, glyceryl behenate, andhydrogenated vegetable oil. These lubricants should be present inamounts from about 0.1%-10% (w/w), with a preferred range of about0.3%-3.0% (w/w).

Tablets are formed, for example, as follows. The pellets are introducedinto a blender along with AVICEL®, disintegrants and lubricant, mixedfor a set number of minutes to provide a homogeneous blend which is thenput in the hopper of a tablet press with which tablets are compressed.The compression force used is adequate to form a tablet; however, it isnot sufficient to fracture the beadlets or coatings.

A pharmaceutical formulation for the delivery of trospium chloride forthe effective treatment of urinary frequency, urgency, nocturia, andurge-incontinence associated with detrusor instability, urge syndrome,and/or detrusor hyperreflexia in a human patient comprising an extendedrelease composition that provides an extended release upon oraladministration to said patient; and a pharmaceutical acceptable carrier;wherein the pharmaceutical formulation is sufficient to maintain aneffective level of trospium chloride in the patient over the course ofat least 12 hours without further administration of trospium chloride.The total dosage of trospium chloride may be about 30 mg to 70 mgproducing in a human patient a plasma concentration versus time curvehaving an area under the curve of about 30,000 pg-Hr/ml to about 80,000pg-Hr/ml. The plasma concentration may have a maximum concentration ofabout 1.5 ng/ml to about 6.0 ng/ml. The plasma concentration may have aminimum concentration of about 0.5 ng/ml to about 1.5 ng/ml. The maximumconcentration of value of the said plasma concentration curve may bereached in about 3 to about 24 hours after oral administration.

A pharmaceutical formulation for the delivery of trospium chloride forthe effective treatment of urinary frequency, urgency, nocturia, andurge-incontinence associated with detrusor instability, urge syndrome,and/or detrusor hyperreflexia in a human patient comprising an extendedrelease composition that provides a delayed release upon oraladministration to said patient; and a pharmaceutical acceptable carrier;wherein the pharmaceutical formulation is sufficient to maintain aneffective level of trospium chloride in the patient over the course ofat least 12 hours without further administration of trospium chloride.The total dosage of trospium chloride may be about 30 to 70 mg producingin a human patient a plasma concentration versus time curve having anarea under the curve of about 30,000 pg/ml*hr l to about 80,000pg/ml*hr. The plasma concentration may have a maximum concentration ofabout 1.5 ng/ml to about 6.0 ng/ml. The plasma concentration may have aminimum concentration of about 0.5 ng/ml to about 1.5 ng/ml. The maximumconcentration of value of the said plasma concentration curve may bereached in about 3 to about 24 hours after oral administration.

A pharmaceutical formulation for the delivery of trospium chloride forthe effective treatment of urinary frequency, urgency, nocturia, andurge-incontinence associated with detrusor instability, urge syndrome,and/or detrusor hyperreflexia in a human patient comprising an immediaterelease and/or an extended release composition that provides animmediate release and/or an extended release upon oral administration tosaid patient; a delayed release composition that provides delayedrelease upon oral administration to said patient; and a pharmaceuticalacceptable carrier; wherein the pharmaceutical formulation is sufficientto maintain an effective level of trospium chloride in the patient overthe course of at least 12 hours without further administration oftrospium chloride, and a peak plasma concentration of the trospiumchloride reached after release of said delayed release compositionexceeds the peak plasma concentration previously reached after releaseof said immediate release composition or extended release composition.The total dosage of trospium chloride may be about 30 to 70 mg producingin a human patient a plasma concentration versus time curve having anarea under the curve of about 30,000 pg/ml*hr to about to about 80,000pg/ml*hr. The plasma concentration may have a maximum concentration ofabout 1.5 ng/ml to about 6.0 ng/ml. The plasma concentration may have aminimum concentration of about 0.5 ng/ml to about 1.5 ng/ml. The maximumconcentration of value of the said plasma concentration curve may bereached in about 3 to about 24 hours after oral administration.

A once a day pharmaceutical formulation of trospium chloride comprisingan immediate release or an extended release composition combined with adelayed release composition wherein the formulation composition containssufficient trospium chloride to obtain a mean blood plasma trospiumconcentration in a human patient is about 500 pg/mL to about 800 pg/mLwithin about 1-3 hour of oral administration; A plasma concentrationversus time of the said once a day formulation has an area under thecurve of about 30,000 pg/ml*hr to about 80,000 pg/ml*hr. The maximumconcentration of said plasma concentration curve is about 1.5 ng/mL toabout 6.0 ng/mL. The T_(max) is about 5 and about 6 hours. The totaltrospium chloride dose is about 30 mg to 80 mg per dose. The immediaterelease or the extended release composition has a release of trospiumchloride equal to about 5% to about 20% of the total dose content within2 hours as measured in an in vitro dissolution test using an USPApparatus II at 50 RPM in 950 ml 50 mM phosphate buffer at a pH between6.8 and 7.5 at 37° C. Said immediate release or an extended releasecomposition combined with a delayed release composition may be in asingle unit or in separate units. Said unit or units may be erodiblematrix systems, coated systems, osmotic systems or combinations thereof.

The invention contemplates a pharmaceutical composition suitable for aonce-a-day administration of trospium chloride comprising an amount ofsolid, trospium chloride-bearing particulates, each particulateincluding one or more trospium chloride-release-controlling substances,such that once-a-day administration of said pharmaceutical compositionprovides steady state (i.e., not single dose but after at least a fewdaily doses, or starting approximately between about 72 hours to about120 hours of continuous once daily dosing) blood levels of trospium,which are substantially equivalent to steady state blood levels oftrospium achieved with twice daily administration of the available 20 mgimmediate release trospium chloride tablets, provided that said solid,trospium chloride-bearing particulates cannot comprise trospiumchloride-release-controlling substances selected exclusively fromimmediate release substances.

In a preferred embodiment of the invention the once-a-day administrationof the controlled release pharmaceutical composition provides steadystate blood levels of trospium falling in the range of about 0.5 ng/mlto about 6.0 ng/ml, and preferably, for the dosage level correspondingto the 20 mg bid regimen of trospium chloride, falling in the range ofabout 0.75 ng/ml to about 3.0 ng/ml. It will be understood by cliniciansand others skilled in the art that patients may be titrated up or downfrom the conventional 20 mg bid trospium chloride dosage, in which casethe dosage units of the present invention would be correspondinglyadjusted. The range of drug concentration in the formulations of thepresent invention accounts for such adjustments, it being understoodthat the preferred drug ranges roughly correspond to the typical 20 mgbid dosage regimen.

The invention is also contemplated to provide a pharmaceuticalcomposition in which once-a-day administration provides steady stateblood C_(max) levels of trospium falling in the range of about 2.5 ng/mlto about 4.5 ng/ml and C_(min) levels of trospium falling in the rangeof about 0.5 ng/ml to about 1.5 ng/ml. Moreover, the invention providespharmaceutical compositions in which once-a-day administration providessteady state areas under the curve falling in the range of about 30 toabout 60 ng/ml*hr, preferably, falling in the range of about 35 to about45 ng/ml*hr.

In a particular embodiment of the invention, pharmaceutical compositionsare provided in which once-a-day administration provides steady state %F (i.e., relative bioavailability) values falling in the range of about80 to about 120, preferably, falling in the range of about 90 to about110.

Hence, the invention contemplates that a wide selection of one or moretrospium chloride-release-controlling substances is selected forinclusion in the solid, trospium chloride-bearing particulates,including, for example, one or more trospiumchloride-release-controlling substances selected from substances thatprovide for immediate release, delayed release, extended release, orpH-sensitive release of trospium chloride, provided that if an immediaterelease substance is selected, then the pharmaceutical composition alsoincludes one or more delayed release, extended release, pH-sensitiverelease substances or combinations thereof.

Specific embodiments, described in further detail in the examples,include but are not limited to formulations that are designated DR1,DR2, XR, XR1-1, XR1-2, XR1+DR2 and IR/DR2, to name a few.

The invention also contemplates a method of treating a mammal sufferingfrom a condition that would benefit from a once daily administration ofan effective amount of trospium chloride, comprising administering to amammal in need thereof a once-a-day formulation comprising an effectiveamount of trospium chloride which provides steady state blood levels oftrospium, which are substantially equivalent to steady state bloodlevels of trospium achieved with twice daily administration of 20 mg bidimmediate release trospium chloride tablets (or a corresponding titrateddose) and which will lessen side effects. The invention now will bedescribed in particularity with the following illustrative examples;however, the scope of the present invention is not intended to be, andshall not be, limited to the exemplified embodiments below.

This invention provides profiles that would make an acceptableonce-a-day dosing regimen for trospium chloride. Trospium chloride is ahighly water-soluble compound with a saturation solubility of 500 mg/ml.This invention overcomes the challenge imposed by highly water-solubledrugs as the active pharmaceutical ingredient in extended releasepreparations. Once-a-day dosing has a decided advantage over multipledosing, increasing, for example, the rates of patient compliance. Also,once-a-day dosing with controlled release formulations reduces the sideeffects associated with spikes in the plasma concentration, which followthe multiple dose administration of immediate release formulations.

Thus, the present invention is also directed to methods of treating amammal, preferably human, by administering once a day a compositionaccording to the present invention, which will give average steady stateblood levels of trospium of a minimum of about 0.5 ng/ml and a maximumof about 6.0 ng/ml, and preferably between about 0.75 and about 5.0ng/ml. Any of the various compositions described in this application canaccomplish those blood levels, an achievement not previously thoughtpossible. Schröder, S. et al., vide supra.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and notintended to be limiting.

EXAMPLES Example 1 Trospium Chloride Immediate Release Pellets

Trospium chloride immediate release (IR) pellets were manufactured bycoating 30/35-mesh sugar spheres with trospium chloride from a coatingdispersion consisting of trospium chloride, hydroxypropylmethylcellulose(HPMC E5, a binder), talc (an anti-tacking agent), and water in aGlatt's® GPCG-1 fluid bed coater. Table 1 provides the formulacomposition of trospium chloride IR capsules, as well as modifiedrelease compositions, and Table 2 sets forth the composition of thepellets. The drug layering dispersion is prepared by dissolving the HPMCE5 in water, dissolving the trospium chloride therein, then dispersingthe talc, and stirring for 20 minutes. The resulting dispersion wasstirred throughout the coating process to prevent settling of coatingcomponents. Coating parameters for Glatt's® GPCG-1 are given in Table 3.The pellets generated contained about 20% w/w of trospium chloride.

The procedure followed to determine the dissolution profiles was:

FIG. 1: USP Apparatus II, 50 RPM. Media: 950 ml 0.1N HCl, pH 1.1;

FIG. 2: USP Apparatus II, 50 RPM. Media: 950 ml 50 mM phosphate buffer,pH 7.5;FIG. 3: USP Apparatus II, 50 RPM. Media: 750 ml 0.1N HCl pH 1.1 for thefirst 2 Hrs and then media adjusted to pH 6.8 at 2 Hrs using phosphatebuffer (total media volume=950 ml);FIG. 4: USP Apparatus II, 50 RPM. Media: 950 ml 50 mM phosphate buffer,pH 7.5;FIG. 5: USP Apparatus II, 50 RPM. Media: 950 ml 50 mM phosphate buffer,pH 7.5;FIG. 6: USP Apparatus II, 50 RPM. Media: 750 ml 0.1 N HCl pH 1.1 for thefirst 2 Hrs and then media adjusted to pH 6.8 at 2 Hrs using phosphatebuffer (total media volume=950 ml);FIG. 7 USP Apparatus II, 50 RPM. Media: 750 ml 0.1N HCl pH 1.1 for thefirst 2 Hrs and then media adjusted to pH 7.5 at 2 Hrs using phosphatebuffer (total media volume=950 ml);FIG. 8: USP Apparatus II, 50 RPM. Media: 750 ml 0.1N HCl pH 1.1 for thefirst 2 Hrs and then media adjusted to pH 7.5 at 2 Hrs using phosphatebuffer (total media volume=950 ml).

FIG. 1 shows the dissolution profiles for the immediate release trospiumchloride pellets in 0.1 N HCl, pH 1.1. The profiles show a releasegreater than about 90% in about 15 minutes.

FIG. 2 shows the dissolution profiles for the extended release trospiumchloride pellets in phosphate buffer, pH 6.8. The profiles show arelease between about 25% and about 80% in about 4 hours, between about50% and about 95% in about 8 hours, between about 70% and about 98% inabout 12 hours and between about 90% and about 100% in 24 hours.

FIG. 3 shows the dissolution profiles for the delayed release trospiumchloride pellets in 0.1N HCl and phosphate buffer, pH 6.8. The profilesshow a release below 1% in acidic media and a release greater than about90% in about 15 minutes after changing the pH

FIG. 4 shows the mean dissolution profiles for the extended release 40mg trospium chloride pellets in phosphate buffer, pH 6.8. The profilesshow a release of less than 10% in about 2 hours, between about 20% andabout 30% in about 4 hours, between about 50% and about 60% in about 8hours, between about 70% and about 80% in about 12 hours and betweenabout 90% and about 100% in 24 hours.

FIG. 5 shows the mean dissolution profiles for the extended release 50mg trospium chloride pellets in phosphate buffer, pH 6.8. The profilesshow a release of less than 10% in about 2 hours, between about 20% andabout 30% in about 2 hours, between about 40% and about 60% in about 4hours, between about 80% and about 90% in about 8 hours and betweenabout 90% and about 100% in 12 hours.

FIG. 6 shows the mean dissolution profile for delayed release 35 mgtrospium chloride pellets in 0.1N HCl and phosphate buffer, pH 6.8. Theprofiles show a release below 1% in acidic media and a release greaterthan about 40% in about 15 minutes after changing the pH, greater than80% in 30 minute after changing the pH and greater than 90% within anhour after changing the pH.

FIG. 7 shows the mean dissolution profile for delayed release 40 mgtrospium chloride pellets in 0.1N HCl and phosphate buffer, pH 6.8. Theprofiles show a release below 1% in acidic media and a release greaterthan about 30% in about 30 minutes after changing the pH, greater than60% release in about 60 minutes after changing the pH and greater than80% release within an hour after changing the pH and greater than 90%release within about 4 hour after changing the pH.

FIG. 8 shows the mean dissolution profile for extended release/delayedrelease 60 mg trospium chloride pellets in 0.1N HCl and phosphatebuffer, pH 6.8. The profiles show a release between about 10% and about20% during the first two hours in acidic media, and a release between30% and 40% in about 30 minutes after changing the pH, between 60% and70% release in about 1 hour after changing the pH, between 60% and 80%release in about 2 hours after changing the pH, between 70% and 80%release in about 4 hours after changing the pH, between 80% and 90%release in about 6 hours after changing the pH and greater than 90%release after a period of about 8 hours after changing the pH.

All the dissolution profiles are generated at 37° C.

TABLE 1a Percent weight composition of trospium chloride dosage forms IRDR1 DR2 XR1 Quantity Quantity Quantity Quantity per unit per unit perunit per unit Components (mg) % (mg) % (mg) % (mg) % Trospium Chloride40 13.64 40 9.13 40 9.23 40 11.97 Sugar Spheres, NF 152 51.84 152.134.71 152 35.07 152 45.48 Hydroxypropyl 2 0.68 2 0.46 2 0.46 2 0.6methylcellulose, USP (Methocel ® E5 Premium LV) Eudragit ® L30D-55 N/AN/A 110.4 25.19 N/A N/A N/A N/A Eudragit ® FS30D N/A N/A N/A N/A 10023.07 N/A N/A Triethyl Citrate, NF N/A N/A 16.6 3.79 5.6 1.29 N/A N/AOpadry ® White, 4 1.36 10.9 2.49 10.8 2.49 8.8 2.63 YS-1-7003 Talc, USP2 0.68 13 2.97 29.8 6.88 2 0.6 Ethyl Cellulose-based N/A N/A N/A N/A N/AN/A 36.2 10.83 Coating Dispersion (Surelease ® Clear) Hard Gelatin 93.231.79 93.2 21.27 93.2 21.50 93.2 27.89 Capsules #0, White Opaque Total293.2 100 438.2 100 433.4 100 334.2 100

TABLE 1b Percent weight composition of trospium chloride dosage forms 60mg 35 mg DR1 40 mg XR1-1 50 mg XR1-2 XR1:DR2 Capsules Capsules CapsulesCapsules Quantity Quantity Quantity Quantity per per per per unit unitunit unit Component (mg) % (mg) % (mg) % (mg) % Trospium Chloride 359.13 40 11.07 50 11.17 60 11.09 Sugar Spheres, NF 133 34.71 152 42.06190 42.46 228 42.16 Hydroxypropyl 1.8 0.46 2 0.55 2.5 0.56 3 0.55methylcellulose, USP (METHOCEL ® E5 Premium LV) EUDRAGIT ® 96.5 25.19N/A N/A N/A N/A N/A N/A L30D55 EUDRAGIT ® N/A N/A N/A N/A 75 13.87 FS30DTriethyl Citrate, NF 14.5 3.79 N/A N/A N/A N/A 4.2 0.78 OPADRY ® White,9.5 2.49 9.1 2.52 11.9 2.66 14.7 2.72 YS-1-7003 Talc, USP 11.4 2.97 20.55 2.5 0.56 23.8 4.4 Ethyl Cellulose- N/A N/A 51.3 14.19 85.6 19.1327.1 5.01 based Coating Dispersion (SURELEASE ® Clear) Hard Gelatin 10521.27 105 29.05 105 23.46 105 19.42 Capsules #0el, White Opaque Total406.7 100 361.4 100 433.4 100 540.8 100

TABLE 2 Percent weight composition of trospium chloride pellets IR DR1DR2 XR1 Components % % % % Trospium Chloride 20 11.59 11.76 16.6 SugarSpheres, NF 76 44.09 44.68 63.08 Hydroxypropyl 1 0.58 0.59 0.83methylcellulose, USP (METHOCEL ® E5 Premium LV) EUDRAGIT ® L30D-55 N/A32 N/A N/A EUDRAGIT ® FS30D N/A N/A 29.39 N/A Triethyl Citrate, NF N/A4.81 1.65 N/A OPADRY ® White, YS- 2 3.16 3.17 3.66 1-7003 Talc, USP 13.77 8.76 0.83 Ethyl Cellulose-based N/A N/A N/A 15 Coating Dispersion(SURELEASE ® Clear) Total 100 100 100 100

TABLE 3 Coating process parameters Parameter GPCG-1 Inlet airtemperature (° C.) 50-55 Product temperature (° C.) 40-42 Atomizationair (bar) 1.5 Spray rate (g/min)  8-12

Example 2 Trospium Chloride Extended Release Pellets

The composition of trospium chloride XR pellet filled capsules isprovided in Table 1. Trospium chloride XR pellets were manufactured bycoating trospium chloride immediate release pellets with a Surelease®Clear coating dispersion using a Glatt® fluid bed coater. Surelease®Clear is a 25% w/w aqueous dispersion supplied by Colorcon (West Point,Pa.). The Surelease® Clear coating dispersion was prepared by addingwater to Surelease® Clear and mixing for 20 minutes to achieve a 20% w/wdispersion of Surelease® Clear. This 20% w/w Surelease® Clear dispersionwas used for coating. The resulting dispersion was stirred throughoutthe coating process to prevent settling of coating components. Variouscoating levels of Surelease® Clear were examined with the objective ofachieving extended release pellets with different extents of delay incoating dissolution, which are shown in Table 4. FIG. 2 shows thedissolution profiles for ethylcellulose coated trospium pellets.

TABLE 4 Composition of trospium chloride extended release pellets 15%w/w 20% w/w 22.5% w/w 25% w/w 27.5% w/w 30% w/w Material SureleaseSurelease Surelease Surelease Surelease Surelease Trospium chloride 16.616.0 15.5 15.0 14.5 14.0 Methocel E5 0.83 0.8 0.78 0.75 0.73 0.7 (HPMC)Sugar Spheres NF 63.08 60.8 58.9 57.0 55.1 53.2 30/35 mesh Altaic 300V(Talc 0.83 0.8 0.78 0.75 0.73 0.7 USP) Surelease Clear 15 20.0 22.5 25.027.5 30 E-7-19010 Opadry White 3.66 1.6 1.55 1.5 1.45 1.4 YS-1-7003

Example 3 Trospium Chloride Delayed Release Pellets

The composition of trospium chloride DR pellet filled capsules isprovided in Table 1. Table 2 provides the composition of delayed releasepellets. Trospium chloride immediate release pellets were coated withEudragit® L30D55 from a coating dispersion consisting of Eudragit®L30D55, triethylcitrate (a plasticizer), talc (an anti-tacking agent),and water using a Glatt® fluid bed coater. Eudragit® L30D55 is a 30% w/waqueous dispersion supplied by Rohm America (Piscataway, N.J.). TheEudragit® L30D55 coating dispersion was prepared by dispersing talc inwater and mixing for at least 20 minutes. Eudragit®L30D55 dispersion wassieved through an 80-mesh sieve. Triethylcitrate was added to theEudragit®L30D55 dispersion and mixed for at least 30 minutes. The talcdispersion was then slowly poured into the Eudragit® L30D55/TECdispersion and mixed for at least 30 minutes. The resulting dispersion(an 11.7% w/w Eudragit® L30D55 aqueous dispersion) was filtered throughan 80-mesh sieve and stirred throughout the coating process to preventsettling of coating components. Various coating levels ofEudragit®L30D55 were examined with the objective of achieving an acidresistant coating. FIG. 3 shows the dissolution profiles for trospiumchloride delayed release pellets.

Example 4 Combination XR/DR

Extended release pellets were prepared as in Example 2, with a 15% w/wcoating of SURELEASE®. Delayed release pellets were manufactured bycoating immediate release pellets with Eudragit FS30D, in a mannersimilar to Example 3. Eudragit®FS30D is a 30% aqueous dispersionsupplied by Rohm America (Piscataway, N.J.). The Eudragit®FS30D coatingdispersion is 18% w/w Eudragit®FS30D. The enteric coated pellets arecombined with extended release pellets in the XR pellets to DR pelletsratio of 1:1, to achieve a total trospium chloride dose of 60 mg.

Example 5 Trospium Chloride Delayed Release at 35 Mg Strength

Delayed release pellets manufactured by coating immediate releasepellets with Eudragit® L30D55 as described in Example 3 were filled intocapsules at a fill weight that provides 35 mg trospium chloride in thecapsule dosage unit.

Example 6 Single Dose Human Pharmacokinetic Studies

A human trial of four controlled release formulations was conducted. Thestudy compared four controlled release dosage units described in theprevious examples (DR1 40 mg, DR2 40 mg, XR 40 mg and a mixture of 20 mgIR:120 mg DR2) with a 40 mg IR capsule given as once daily single doseand the 20 mg IR tablet (Spasmo-Lyt®, Madaus), which was given twice aday at 12 hour intervals.

FIG. 9 shows the pharmacokinetic profiles of the four once-a-daycontrolled release compositions versus the two immediate releaseproducts. FIG. 10 shows the same data with Formulation D removed forease of comparisons. These data demonstrate that the DR1, XR1 and thecombination of IR/DR2 produced pharmacokinetic profiles and parametersthat are similar to the commercial IR twice a day product (FIGS. 9 and10).

Table 5 presents single dose data on areas under the curve (AUC) overgiven time periods (0-24 hrs and 0-72 hrs) for immediate release product(20 mg bid) and controlled release products (40 mg DR1, 40 mg XR1 and 20mg/120 mg IR/DR2 combination), including % F, which is a measure ofbioequivalence. One can appreciate that at least the DR1 and XRcontrolled release products provide AUC data, which are comparable tothose obtained with twice daily administered 20 mg immediate releasetrospium chloride.

TABLE 5 Single Dose Data for Various Trospium Chloride FormulationsSingle Dose AUC 0-24 AUC 0-72 Formulation (pg · hr/ml) (pg · hr/ml) % F20 mg bid 23820 39831 100 40 mg DR1 23782 35589 89 40 mg XR 24271 3609891 20/120 mg IR/DR2 33244 52905 38

Example 7 Steady State Human Pharmacokinetic Studies

A second human trial was conducted comparing four controlled releaseformulations described in Table 1b with 20 mg IR tablet (Spasmo-Lyt®,Madaus), which was given twice a day at 12 hour intervals.

Table 6 presents steady state data on AUC (over a 72 hour time period),C_(max), C_(min), and % F obtained from the administration of thevarious trospium chloride formulations discussed in the precedingparagraph.

TABLE 6 Steady State Data for Various Trospium Chloride Formulations D EConc A B C 30 mg XR1: 20 mg IR Time 35 mg DR1 40 mg XR1-1 50 mg XR1-2 30mg DR2 BID Tmax (Hr) 5.39 5.38 5.38 5.95 5.3 Cmax (pg/mL) 3164.9 2819.81908.7 2398.2 2978.9 AUClast (Hr*pg/mL) 55025.5 44972.1 42419.8 5206067068.7 AUCINF_obs 64076.8 53637.4 62784.5 63931.2 74294.4 (Hr*pg/mL)Relative BA 94% 67% 51% 52% 100% (normalized)

Example 8 Enteral Administration of a Trospium Chloride PharmaceuticalComposition

A delayed release formulation, according to the method of the invention,is prepared using a trospium salt, such as a fluoride, chloride, bromideor iodide, using a delayed release coating, which releases trospium at apH of about 7.0. For example, an appropriate EUDRAGIT releasecontrolling layer is selected so that the active ingredient is releasedat approximately neutral pH, which coincides substantially with the pHof the lower GI tract (e.g., lower intestine, colon, or both). Otherrelease controlling layers may also be selected with the objective ofproviding a pharmaceutical composition comprising trospium as at leastone active ingredient, which releases trospium in sections of the GItract previously thought not to play a role in the delivery/absorptionof significant amounts of trospium. See, e.g., Schroder, S. et al., inInternational Journal of Clinical Pharmacology and Therapeutics, Vol.42-No. 10/2004 (543-549).

1-77. (canceled)
 78. A pharmaceutical composition suitable for aonce-a-day oral administration of trospium chloride to a human, thecomposition comprising: a plurality of particulates comprising trospiumchloride, said particulates further comprising at least one polymer,said pharmaceutical composition having an in vitro release profile asmeasured by USP Apparatus II, 50 RPM, at 37° C., in an acidic medium of750 mL 0.1 N HCl for the first 2 hours and then adjusting the medium topH 7.5 at 2 hours using phosphate buffer; whereby said in vitro profileis characterized by a release of up to about 20% of the total trospiumchloride during the first two hours in the acidic medium, and a releaseof between about 60% and about 80% of the total trospium chloride about2 hours after said pH adjustment.
 79. The pharmaceutical composition ofclaim 78, comprising a methacrylic acid copolymer.
 80. Thepharmaceutical composition of claim 78, comprising polymers selectedfrom the group consisting of a methacrylic acid copolymer, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, andpolyvinyl acetate phthalate.
 81. The pharmaceutical composition of claim80, wherein said plurality of particulates comprises at least 30 mgtrospium chloride.
 82. The pharmaceutical composition of claim 80,wherein said plurality of particulates comprises at least 40 mg trospiumchloride.
 83. The pharmaceutical composition of claim 80, wherein saidplurality of particulates comprises at least 50 mg trospium chloride.84. The pharmaceutical composition of claim 80, wherein the particulatesare substantially spherical.
 85. The pharmaceutical composition of claim80, wherein upon once daily oral administration to a subject in needthereof provides therapeutically effective amounts of trospium chlorideto treat said subject's condition while reducing the occurrence ofdry-mouth relative to oral, twice-daily administration of 20 mgimmediate release trospium chloride tablets.
 86. The pharmaceuticalcomposition of claim 78, wherein once-a-day administration of saidpharmaceutical composition provides steady state blood levels oftrospium chloride less than about 6.0 ng/mL.
 87. The pharmaceuticalcomposition of claim 78, wherein once-a-day administration of saidpharmaceutical composition provides steady state blood levels oftrospium chloride greater than about 0.5 ng/mL.
 88. The pharmaceuticalcomposition of claim 78, whereby single-dosage administration of saidpharmaceutical composition provides a plasma concentration versus timecurve having an area under the curve (AUC_(0-72 hrs)) of about 30,000pg/ml*hr to about 80,000 pg/ml*hr.
 89. The pharmaceutical composition ofclaim 78, whereby single-dosage administration of said pharmaceuticalcomposition provides blood levels of trospium chloride less than about3.0 ng/mL.
 90. The pharmaceutical composition of claim 80, whereinonce-a-day administration of said pharmaceutical composition providessteady state blood levels of trospium chloride less than about 6.0ng/mL.
 91. The pharmaceutical composition of claim 80, whereinonce-a-day administration of said pharmaceutical composition providessteady state blood levels of trospium chloride greater than about 0.5ng/mL.
 92. The pharmaceutical composition of claim 80, wherebysingle-dosage administration of said pharmaceutical composition providesa plasma concentration versus time curve having an area under the curve(AUC_(0-72 hrs)) of about 30,000 pg/ml*hr to about 80,000 pg/ml*hr. 93.The pharmaceutical composition of claim 80, whereby single-dosageadministration of said pharmaceutical composition provides blood levelsof trospium chloride less than about 3.0 ng/mL.